Bi-aromatic compounds bound by a heteroethynylene radical and pharmaceutical and cosmetic compositions containing same

ABSTRACT

Bi-aromatic compounds linked via a heteroethynylene radical are provided along with pharmaceutical and cosmetic compositions containing these compounds and methods for their use.

This application is a 371 of PCT/FR98/01835 filed Aug. 21, 1998,published as WO 99/10322 Mar. 4, 1999.

The invention relates, as novel and useful industrial products, tobi-aromatic compounds whose aromatic rings are linked via a divalentheteroethynylene radical. The invention also relates to the use of thesenovel compounds in pharmaceutical compositions intended for use in humanor veterinary medicine, or alternatively in cosmetic compositions.

The compounds according to the invention have pronounced activity in thefields of cell differentiation and proliferation and find applicationsmore particularly in the topical and systemic treatment ofdermatological complaints associated with a keratinization disorder,dermatological (or other) complaints with an inflammatory and/orimmunoallergic component, and dermal or epidermal proliferations,whether they are benign or malignant. These compounds can also be usedin the treatment of connective tissue degenerative diseases, forcombating ageing of the skin, whether this is light-induced orchronological ageing, and for treating cicatrization disorders. Theymoreover find an application in the opthalmological field, in particularin the treatment of corneopathy.

The compounds according to the invention can also be used in cosmeticcompositions for body and hair hygiene.

Bi-aromatic compounds whose aromatic rings are linked via a divalentpropynylene have already been described in EP-661,258 as activesubstances in pharmaceutical or cosmetic compositions.

The compounds according to EP-661,258 correspond to the followinggeneral formula:

in which:

Ar is a divalent aromatic radical optionally substituted with a radicalR₅ or a heteroaromatic radical optionally substituted with a radical R₆when the hetero atom is nitrogen,

R₁ represents H, —CH₃, —CH₂OR₆, —OR₆, —COR₇ or —S(O)_(t)R₉, t being 0, 1or 2.

R₂ and R₃ represent H, C₁-C₂₀ alkyl, —OR₆ or —SR₆,

or R₂ and R₃ taken together, form a 5- or 6-membered ring optionallysubstituted with methyl groups and/or optionally interrupted by anoxygen or sulphur atom,

R₄ and R₅ represent H, a halogen, lower alkyl or —OR₆,

R₆ represents H, lower alkyl or —COR₉,

R₇ represents H, lower alkyl,

 or —OR₈,

R₈ represents H, linear or branched C₁-C₂₀ alkyl, alkenyl, mono- orpolyhydroxyalkyl, optionally substituted aryl or aralky, or a sugar oramino acid or peptide residue,

R₉ represents lower alkyl,

R and R′ represent H, lower alkyl, mono- or polyhydroxyalkyl, optionallysubstituted aryl or a sugar, amino acid or peptide residue or R and R′,taken together, form a heterocycle, and

X represents a divalent radical which, from right to left or vice-versa,has the formula:

in which:

R₁₀ represents H, lower alkyl or —OR₆,

R₁₁ represents —OR₆,

or R₁₀ and R₁₁, taken together, form an oxo (═O) radical,

and the salts of the said compounds of the above formula when R₁represents a carboxylic acid function, and the optical and geometricalisomers of these said compounds.

The compounds according to the present invention differ from those ofEP-661,258 essentially in that the radical X or divalent propynyleneradical has been replaced with a divalent heteroethynylene radical.

The reason for this is that it has been found, surprisingly andunexpectedly, that this structural change makes it possible tosignificantly increase the pharmaceutical and cosmetic propertiesthereof and also to decrease certain side effects thereof.

A subject of the present invention is thus novel compounds which can berepresented by the following general formula:

in which:

Ar represents a radical chosen from the formulae (a) to (c) below:

Z being O or S, or N—R₆,

R₁ represents a halogen atom, —CH₃, —CH₂—OR₇, —OR₇, —COR₈ or a polyetherradical,

R₂ and R₃, which may be identical or different, represent H, linear orbranched C₁-C₂₀ alkyl, C₃-C₁₂ cycloalkyl, —OR₇ or —SR₇, at least onefrom among R₂ and R₃ being linear or branched C₁-C₂₀ alkyl or C₃-C₁₀cycloalkyl, or

R₂ and R₃, taken together, form a 5- or 6-membered ring, optionallysubstituted with at least one methyl and/or optionally interrupted by ahetero atom chosen from O and S,

R₄ and R₅ represent H, a halogen atom, linear or branched C₁-C₂₀ alkyl,—OR₇ or a polyether radical,

R₆ represents H, linear or branched C₁-C₁₀ alkyl or —OCOR₉,

R₇ represents H, linear or branched C₁-C₁₀ alkyl or —COR₉,

R₈ represents H, linear or branched C₁-C₁₀, alkyl, —OR₁₀ or

R₉ represents linear or branched C₁-C₁₀ alkyl,

R₁₀ represents H, linear or branched C₁-C₂₀ alkyl, mono- orpolyhydroxyalkyl, allyl, optionally substituted aryl or aralkyl, or asugar residue,

r′ and r″, which may be identical or different, represent H, C₁-C₁₀alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl, an aminoacid or peptide residue, or, taken together with the nitrogen atom, forma heterocycle,

X represents a divalent radical which, from right to left or vice-versa,has the formula:

in which:

Y represents O, S(O)_(n) or Se(O)_(n′),

n and n′ being 0, 1 or 2,

with the proviso that when n=2 and Ar is a radical of formula (a) above,in which R₁=—CH₃ and R₅=H, then at least one of the radicals R₂ or R₃ isother than —CH₃,

and the salts of the compounds of formula (I) when R₁ represents acarboxylic acid function, as well as the optical isomers of the saidcompounds of formula (I).

When the compounds according to the invention are in the form of a salt,this is preferably a salt of an alkali metal or alkaline-earth metal, oralternatively of zinc or of an organic amine.

According to the present invention, the term “C₁-C₁₀ alkyl” preferablyrefers to the methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl,2-ethylhexyl and octyl radicals.

The term “linear or branched C₁-C₂₀ alkyl” refers in particular to themethyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl andoctadecyl radicals.

The term “C₃-C₁₂ cycloalkyl radical” refers to a mono- or polycyclicradical, in particular the cyclopropyl, cyclopentyl, cyclohexyl,1-methylcyclohexyl and 1-adamantyl radicals.

The term “polyether radical” refers to a radical containing from 2 to 5carbon atoms interrupted by at least two oxygen atoms, such as themethoxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.

The term “monohydroxyalkyl” refers to a radical preferably containing 2or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or3-hydroxypropyl radical.

The term “polyhydroxyalkyl” refers to a radical preferably containing 3to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.

The term “aryl” preferably refers to a phenyl radical optionallysubstituted with at least one halogen atom, a hydroxyl or a nitrofunction.

The term “aralkyl” preferably refers to a benzyl or phenethyl radicaloptionally substituted with at least one halogen atom, a hydroxyl or anitro function.

The term “sugar residue” refers to a residue derived in particular fromglucose, from galactose or from mannose, or alternatively fromglucuronic acid.

The term “amino acid residue” refers in particular to a residue derivedfrom lysine, from glycine or from aspartic acid, and the term “peptideresidue” refers more particularly to a dipeptide or tripeptide residueresulting from the combination of amino acids.

The term “heterocycle” preferably refers to a piperidino, morpholino,pyrrolidino or piperazino radical, optionally substituted in position 4with a C₁-C₆ lower alkyl or a mono- or polyhydroxyalkyl as definedabove.

When R₁, R₄ and/or R₅ represents a halogen atom, this is preferably afluorine, chlorine or bromine atom.

According to a first preferred embodiment, the compounds according tothe invention correspond to the following general formula:

in which:

Ar′ represents a radical of formula:

R₁, R₄, R₅ and X being as defined above for formula (I),

R₁₁, R₁₂, R₁₃ and R₁₄, which may be identical or different, represent Hor —CH₃, and

n is 1 or 2.

According to a second preferred embodiment, the compounds according tothe invention correspond to the following formula:

in which:

W represents O or S,

R₄, R₁₁, R₁₂, Ar′ and X being as defined above in the formulae (I) and(II).

Lastly, according to a third preferred embodiment, the compoundsaccording to the invention correspond to the following formula:

in which:

R₄, Ar′ and X are as defined above in formulae (I) to (III), and

at least one of the radicals R′₂ and/or R′₃ represents a mono- orpolycyclic C₅-C₁₀ cycloalkyl radical, the other representing one of themeanings given for R₂ or R₃.

Among the compounds of formulae (I) to (IV) above, according to thepresent invention, mention may be made in particular of the following:

Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphanylethynyl)benzoate,

4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoicacid,

Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphonylethynyl)benzoate,

Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthyloxyethynyl)benzoate,

4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxyethynyl)benzoicacid,

Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphanylethynyl)benzoate,

4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoicacid,

Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphonylethynyl)benzoate,

4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoicacid,

Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphinylethynyl)benzoate,

4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphinylethynyl)benzoicacid,

Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylselanylethynyl)benzoate,

4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

Methyl2-hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

2-Hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

6-(4-Methoxymethoxyphenylethynylselanyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene,

Ethyl6-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylselanylethynyl)nicotinate,

6-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid,

N-(4-Hydroxyphenyl)-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzamide,

Methyl5-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate,

2-(4-Chlorophenylselanylethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,

Methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

Methyl2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

2-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

Ethyl6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid,

N-(4-Hydroxyphenyl)-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide,

N-Butyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide,

Morpholin-4-yl-[6-(3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-3-pyridyl]methanone,

Methyl5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)pyridine-2-carboxylate,

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)pyridine-2-carboxylicacid,

[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]methanol,

Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate,

Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoate,

Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoate,

4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoicacid,

4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoicacid,

4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoicacid,

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol,

Ethyl4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

Ethyl4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl-ethynyl)benzoate,

4-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

4-(4-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

Ethyl4-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl-ethynyl)benzoate,

Ethyl4-(3-methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl-ethynyl)benzoate,

4-(3-Methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl-ethynyl)benzoicacid,

4-(3-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

Ethyl4-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,

4-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid,

[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]carbaldehyde,

Methyl 4-(4,4-dimethylthiochroman-8-ylselanylethynyl)benzoate,

4-(4,4-Dimethylthiochroman-8-ylselanyl-ethynyl)benzoic acid,

Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoate,

4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoicacid,

Methyl 4-[3-(1-adamantyl)-4-methoxyphenyl)-1-ylselanylethynyl]benzoate,

4-[3-(1-Adamantyl)-4-methoxyphenyl)-1-ylselanylethynyl]benzoic acid,

Methyl 4-[4-(1-adamantyl)-3-methoxyphenyl)-1-ylselanylethynyl]benzoate,and

4-[4-(1-Adamantyl)-3-methoxyphenyl)-1-ylselanylethynyl]benzoic acid.

A subject of the present invention is also the processes for preparingthe compounds of formula (I) above according to the reaction schemesgiven in Tables A and B.

With reference to Table A, the compounds of formula (I) in which Xrepresents the divalent radical

i.e. the compounds of formula (Ia), can be obtained according to twodifferent synthetic routes depending on whether Y=oxygen or Y≠oxygen.

When X=oxygen, the starting material is the compound of formula (1),which, in the presence of a base such as potassium hydride or sodiumhydride, is then coupled with trichloroethylene. The dichloroethyleneproduct obtained, of formula (2), is then subjected to the action of alithiated base, such as butyllithium, in a solvent such as THF, to givethe acetylenic compound of formula (3). This acetylene is then coupledwith an aryl halide or a heteroaryl halide, preferably an iododerivative, in the presence of a palladium catalyst to give thecompounds of formula (IIa) with Y=oxygen.

When Y≠oxygen, the lithium acetylide of formula (5) is first prepared,from the aromatic or heteroaromatic acetylenic compound (4), in thepresence of a lithiated derivative such as butyllithium, in a solventsuch as THF. Starting with the lithium acetylide (5), which is notisolated, a coupling is carried out with the compound of formula (6), ina solvent such as THF, to give the compounds of formula (Ia) withY≠oxygen.

Starting with these compounds of formula (Ia) in which Y=S or Se, it ispossible to gain access to the oxidized derivatives by oxidation usingan oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) or sodiumperiodate.

With reference now to Table B, the compounds of formula (I), in which Xrepresents a divalent radical

i.e. the compounds of formula (Ic), can also be obtained according totwo different synthetic routes depending on whether Y=oxygen orY≠oxygen.

When Y=oxygen, the starting material is an aromatic or heteroaromaticcompound of formula (7), which, in the presence of a base such aspotassium hydride or sodium hydride, in a solvent such as THF, is thencoupled with trichloroethylene. The dichloroethylene product obtained(8) is then subjected to the action of a lithiated base such asbutyllithium, in THF, to give the oxoacetylenic compound of formula (9).This acetylene is then coupled with an aryl halide (10), preferably aniodo derivative, in the presence of a palladium catalyst, to give thecompounds of formula (Ic) with Y=oxygen.

When Y≠oxygen, the starting material is an aromatic acetylenic compoundof formula (11), which is converted into a lithiated derivative in thepresence of butyllithium, for example in a solvent such as THF. Thelithiated acetylenic derivative (12), which is not isolated, is thencoupled with an aromatic or heteroaromatic compound of formula (13), thecoupling reaction being carried out in a solvent such as THF. Thecompounds of formula (Ic) with Y≠oxygen are thus obtained by thissynthetic route.

Starting with these compounds of formula (Ic), in which Y=S or Se, it isalso possible to obtain the oxidized derivatives by oxidation using anoxidizing agent such as meta-chloroperbenzoic acid (mCPBA) or sodiumperiodate.

When, in the compounds according to the invention, the radical R₁represents —COOH, these radicals are prepared by protecting thecarboxylic acid function with a protecting group of the alkyl type.

By saponification of the ester function in the presence of a base suchas sodium hydroxide or lithium hydroxide in an alcoholic solvent or inTHF, the corresponding free acids are thus obtained.

When R₁ is —OH, the compounds can be obtained from the correspondingacid by reduction in the presence of hydride such as boron hydride.

When R₁ is —CH═O, the compounds can be obtained by oxidation of thecorresponding alcohols using manganese oxide or pyridinium dichromate.

When R₁ is

the compounds can be obtained by conversion of the corresponding acidinto the acid chloride, for example with thionyl chloride, followed byreaction with aqueous ammonia or a suitable amine.

A subject of the present invention is also the compounds of formula (I)as defined above, as medicinal products.

The compounds of general formula (I) have agonist or antagonist activitywith respect to the expression of one or more biological markers in thetest of differentiation of mouse embryonic teratocarcinoma cells (F9)(Skin Pharmacol. 3, p. 256-267, 1990) and/or on the in vitrodifferentiation of human keratinocytes (Skin Pharmacol. 3, p. 70-85,1990). These abovementioned tests show the activities of the compoundsin the fields of differentiation and proliferation. The activities canalso be measured in cellular transactivation tests using RAR recombinantreceptors according to the method by B. A. Bernard et al., Biochemicaland Biophysical Research Communication, vol. 186, 977-983, 1992.

The compounds according to the invention are particularly suitable inthe following fields of treatment:

1) for treating dermatological complaints associated with akeratinization disorder which has a bearing on differentiation and onproliferation, in particular for treating common acne, comedones,polymorphonuclear leukocytes, rosacea, nodulocystic acne, acneconglobata, senile acne and secondary acne such as solar,medication-related or occupational acne,

2) for treating other types of keratinization disorder, in particularichthyosis, ichthyosiform states, Darier's disease, palmoplantarkeratoderma, leucoplasias and leucoplasiform states, and cutaneous ormucous (buccal) lichen,

3) for treating other dermatological complaints associated with akeratinization disorder with an inflammatory and/or immunoallergiccomponent and, in particular, all forms of psoriasis, whether it iscutaneous, mucous or ungual psoriasis and even psoriatic rheumatism, oralternatively cutaneous atopy, such as eczema or respiratory atopy oralternatively gingival hypertrophy; the compounds can also be used incertain inflammatory complaints which have no keratinization disorder;

4) for treating all dermal or epidermal proliferations, whether benignor malignant and whether they are of viral origin or otherwise, such ascommon warts, flat warts and verruciform epidermodysplasia, it beingalso possible for the oral or florid papillomatoses and theproliferations to be induced by ultraviolet radiation, in particular inthe case of basocellular and spinocellular epithelioma,

5) for treating other dermatological disorders such as bullosis andcollagen diseases,

6) for treating certain ophthalmological disorders, in particularcorneopathies,

7) for repairing or combating ageing of the skin, whether this islight-induced or chronological ageing, or for reducing actinic keratosesand pigmentations, or any pathologies associated with chronological oractinic ageing,

8) for preventing or curing the stigmata of epidermal and/or dermalatrophy induced by local or systemic corticosteroids, or any other formof cutaneous atrophy,

9) for preventing or treating cicatrization disorders or for preventingor repairing stretch marks,

10) for combating disorders of sebaceous functioning such as thehyperseborthoea of acne or simple seborrhoea,

11) in the treatment or prevention of cancerous or precancerous states,

12) in the treatment of inflammatory complaints such as arthritis,

13) in the treatment of any general or skin complaint of viral origin,

14) in the prevention or treatment of alopecia,

15) in the treatment of dermatological or general complaints having animmunological component, and

16) in the treatment of complaints of the cardiovascular system such asarteriosclerosis.

In the therapeutic fields mentioned above, the compounds according tothe invention may be employed advantageously in combination with othercompounds of retinoid-type activity, with D vitamins or derivativesthereof, with corticosteroids, with anti-free-radical agents, α-hydroxyor α-keto acids or derivatives thereof, or alternatively withion-channel blockers. The expression “D vitamins or derivatives thereof”means, for example, vitamin D₂ or D₃ derivatives and in particular1,25-dihydroxyvitamin D₃. The expression “anti-free-radical agents”means, for example, α-tocopherol, superoxide dismutase or SOD, ubiquinolor certain metal-chelating agents. The expression “α-hydroxy or α-ketoacids or derivatives thereof” means, for example, lactic, malic, citric,glycolic, mandelic, tartaric, glyceric or ascorbic acid or the salts,amides or esters thereof. Lastly, the term “ion-channel blockers” means,for example, Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) andderivatives thereof.

A subject of the present invention is also pharmaceutical compositionscontaining at least one compound of formula (I) as defined above, one ofthe optical or geometrical isomers thereof or one of the salts thereof.

The pharmaceutical compositions are intended in particular for treatingthe abovementioned complaints, and are characterized in that theycomprise a pharmaceutically acceptable support which is compatible withthe mode of administration selected, at least one compound of formula(I), one of the optical or geometrical isomers thereof or one of thesalts thereof.

The compounds according to the invention may be administered enterally,parenterally, topically or ocularly.

Via the enteral route, the compositions may be in the form of tablets,gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions,powders, granules, emulsions, microspheres or nanospheres or polymericor lipid vesicles which enable controlled release. Via the parenteralroute, the compositions may be in the form of solutions or suspensionsfor infusion or for injection.

The compounds according to the invention are generally administered at adaily dose of about 0.01 mg/kg to 100 mg/kg of body weight taken in 1 to3 doses.

Via the topical route, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended forthe treatment of the skin and the mucosae and may then be in the form ofointments, creams, milks, salves, powders, impregnated pads, solutions,gels, sprays, lotions or suspensions. They may also be in the form ofmicrospheres or nanospheres or polymeric or lipid vesicles or polymericpatches and hydrogels which enable controlled release of the activeprinciple. Furthermore, these topical-route compositions may either bein anhydrous form or in aqueous form, depending on the clinicalindication.

Via the ocular route, they are mainly eyedrops.

These compositions for topical or ocular use contain at least onecompound of formula (I) as defined above, or one of the optical orgeometrical isomers thereof or alternatively one of the salts thereof,at a concentration preferably of between 0.001% and 5% by weightrelative to the total weight of the composition.

The compounds of formula (I) according to the invention also find anapplication in the cosmetic field, in particular in body and hairhygiene and especially for treating skin types with a tendency towardsacne, for promoting the regrowth of the hair, for combating hair loss,for combating the greasy appearance of the skin or the hair, inprotection against the harmful effects of the sun or in the treatment ofphysiologically dry skin types, and for preventing and/or combatinglight-induced or chronological ageing.

In the cosmetic field, the compounds according to the invention canmoreover be employed advantageously in combination with other compoundsof retinoid-type activity, with D vitamins or derivatives thereof, withcorticosteroids, with anti-free-radical agents, α-hydroxy or α-ketoacids or derivatives thereof, or alternatively with ion-channelblockers, all of these latter compounds being as defined above.

The present invention is thus also directed towards a cosmeticcomposition which is characterized in that it comprises, in acosmetically acceptable support, at least one compound of formula (I) asdefined above or one of the optical or geometrical isomers thereof orone of the salts thereof, it being possible for the said cosmeticcomposition to be, in particular, in the form of a cream, a milk, alotion, a gel, microspheres or nanospheres or polymeric or lipidvesicles, a soap or a shampoo.

The concentration of compound of formula (I) in the cosmeticcompositions according to the invention is advantageously between 0.001%and 3% by weight relative to the total weight of the composition.

The pharmaceutical and cosmetic compositions according to the inventioncan also contain inert additives or even pharmacodynamically orcosmetically active additives or combinations of these additives and, inparticular: wetting agents; depigmenting agents such as hydroquinone,azelaic acid, caffeic acid or kojic acid; emollients; moisturizingagents such as glycerol, PEG-400, thiamorpholinone and derivativesthereof, or urea; anti-seborrhoea or anti-acne agents such asS-carboxymethylcysteine, S-benzylcysteamine, the salts or derivativesthereof, or benzoyl peroxide; antibiotics such as erythromycin andesters thereof, neomycin, clindamycin and esters thereof, andtetra-cyclines; antifungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolidones; agents for promoting the regrowthof the hair, such as Minoxidil(2,4-diamino-6-piperidinopyrimidine-3-oxide) and derivatives thereof,Diazoxide (7-chloro-3-methyl-1,2,4-benzo-thiadiazine 1,1-dioxide) andPhenytoin (5,4-diphenyl-imidazolidine-2,4-dione); non-steroidalanti-inflammatory agents; carotenoids and, in particular, β-carotene;anti-psoriatic agents such as anthraline and derivatives thereof and,lastly, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoicacid, the esters and amides thereof.

The compositions according to the invention may also containflavour-enhancing agents, preserving agents such as para-hydroxybenzoicacid esters, stabilizing agents, moisture regulators, pH regulators,osmotic pressure modifiers, emulsifying agents, UV-A and UV-B screeningagents, and antioxidants such as α-tocopherol, butylated hydroxyanisoleor butylated hydroxytoluene.

Several examples for obtaining the active compounds of formula (I)according to the invention, as well as various cosmetic andpharmaceutical formulations based on such compounds, will now be givenfor illustrative purposes and with no limiting nature.

EXAMPLES Example 1 Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)-benzoate(a) Methyl 4-trimethylsilylethynylbenzoate

21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml of triethylamine anda mixture of 200 mg of palladium acetate and 400 mg oftriphenylphosphine are introduced into a three-necked flask. 20 g (0.204mol) of trimethylsilylacetylene are then added, after which the mixtureis heated gradually to 90° C. over 1 hour and left at this temperaturefor 5 hours. The reaction medium is then cooled, the salt is filteredoff and the filtrate is evaporated. The residue is taken up in 200 ml ofhydrochloric acid (5%) and 400 ml of ethyl ether. The ether phase isseparated out after settling has taken place, washed with water, driedover magnesium sulphate and evaporated. The residue obtained is purifiedby chromatography on a column of silica eluted with dichloromethane.After evaporation of the solvents, 23 g (100%) of the expectedderivative are collected in the form of a colourless oil.

(b) Methyl 4-ethynylbenzoate

38.33 g (226 mmol) of the product obtained above in 300 ml of methanolare introduced into a three-necked flask. 125 g of potassium carbonateare then added and the medium is stirred for 48 hours at roomtemperature. The solvent is evaporated off and the residue obtained ispurified by chromatography on a column of silica eluted withdichloromethane. After evaporation of the solvents, the residue is takenup in heptane and, after filtration, 32 g (100%) of the expectedderivative are collected in the form of a straw-yellow solid.

(c) Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate

A 2.5 M solution of butyllithium in hexane (20 mmol, 8.1 ml) is added toa solution of methyl 4-ethynylbenzoate (3 g, 18.7 mmol) in THF (300 ml)at −78° C. The temperature is maintained for 45 minutes and is thenraised to −40° C. A solution of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene disulphide (J. Med.Chem. 1995, 38, 3171) (16.5 g, 37.4 mmol) in THF (60 ml) is then addedat this temperature. The reaction medium is then stirred for 1 hour at0° C., after which it is poured into a mixture of ethyl ether andsaturated ammonium chloride solution. The organic phase is washed twicewith water, dried over anhydrous magnesium sulphate and concentrated ona rotary evaporator under vacuum at 40° C. After chromatography on acolumn of silica, using a mixture of heptane/methylene chloride (60/40),and after evaporation, 1.9 g of a white solid (27%) are obtained.

¹H (CDCl₃): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 3.92 (3H, s), 7.25to 7.31 (2H Ar, m), 7.42 (1H Ar, d, J=2 Hz), 7.50 (1H, Ar, d, J=7.5 Hz),8.00 (1H, Ar, d, J=7.5 Hz).

13_(C) (CDCl₃) 32.25 (CH₃), 34.60 (C), 35.02 (C), 35.36 (CH₂), 52.68(OCH₃). 81.26 (C), 96.96 (C), 124.82 (CH Ar), 125.56 (CH Ar), 128.29 (CAr), 128.37 (CH Ar), 128.85 (C Ar), 129.88 (C Ar), 130.04 (2 CH Ar),131.29 (2 CH Ar), 144.66 (C, Ar), 146.88 (C Ar), 166.95 (COO).

Example 24-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoicacid

A solution of methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate(590 mg, 1.6 mmol) and of lithium hydroxide (383 mg, 9.3 mmol) in THF isrefluxed for 24 hours. The reaction mixture is poured into an Et₂O/watermixture, acidified to pH 1 with concentrated hydrochloric acid solution,and extracted once with ethyl ether. After separation of the phases bysettling, the organic phase is washed twice with water, dried overmagnesium sulphate and concentrated on a rotary evaporator under vacuumat 40° C. The solid obtained is crystallized from heptane and 440 mg(77%) of a white solid are obtained. m.p. (melting point)=193.5° C.

NMR δ ppm:

¹H (CDCl₃): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 7.29 to 7.32 (2HAr, m), 7.42 (1H Ar, d, J=2 Hz), 7.53 (1H Ar, d, J=8, 5 Hz), 8.08 (1HAr, d, J=8.5 Hz).

13_(C) (CDCl₃): 31.44 (CH₃), 33.80 (C), 34.22 (C), 34.54 (CH₂), 81.30(C), 100.01 (C), 124.06 (CH Ar), 124.81 (CH Ar), 127.59 (CH Ar), 127.94(C Ar), 128.46 (C Ar), 129.87 (2 CH Ar), 130.49 (2 CH Ar), 143.93 (CAr), 146.12 (C Ar), 171.06 (COO).

Example 3 Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoate

A solution of meta-perbenzoic acid (700 mg) in CHCl₃ (12 ml) is addeddropwise, at 0° C., to a solution of the product of Example 1 (500 mg,1.3 mmol) in 6 ml of CHCl₃. After stirring for 1 hour, the mixture isconcentrated on a rotary evaporator under vacuum. After chromatographyon a column of silica with a heptane/methylene chloride mixture (30/70),280 mg of a white solid are obtained (52%).

¹H (CDCl₃): 1.32 (6H, s), 1.34 (6H, s), 1.73 (4H, s), 3.93 (3H, s), 7.51(2H Ar, d, J=8.3 Hz), 7.60 (2H Ar, d, J=8.5 Hz), 7.78 (1H Ar, dd, J1=8.5Hz, J2=2 Hz), 7.98 to 8.05 (3H Ar, m). 13_(C) (CDCl₃): 31.63 (CH₃),31.73 (CH₃), 34.58 (CH₂), 34.64 (CH₂), 34.85 (C), 34.98 (C), 52.52(CH₃), 87.77 (C), 90.99 (C), 122.61 (C Ar), 124.35 (CH Ar), 125.99 (CHAr), 128.04 (CH Ar), 129.68 (CH Ar), 132.44 (C Ar), 132.69 (CH Ar),138.37 (C Ar), 152.50 (C Ar), 165.83 (COO).

Example 4 Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate(a) 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalene diselenide

A 1.7 M solution of tert-butyllithium in pentane (37.4 mmol, 22 ml) isadded to a solution of2-bromo-5,6,7,8-tetrahydro-5,5,8,8-teramethyl-naphthalene (4.22 g, 15.8mmol) in THF (100 ml) at −78° C. over 10 min. The mixture is stirred at0° C. for 30 min. Selenium (1.33 g, 16.8 mmol) is added in two portions.The mixture is stirred at 0° C. for 15 min and then at room temperaturefor 30 min. 1N HCl solution (40 ml) is added and the reaction mixture isthen treated with ethyl ether. The organic phase is washed twice withwater, dried over anhydrous magnesium sulphate and concentrated on arotary evaporator under vacuum at 40° C. 10 ml of ethanol and 50 mg ofsodium hydroxide are added to the oil obtained. The mixture is stirredvigorously for a few minutes and is then concentrated on a rotaryevaporator under vacuum at 40° C. The solid obtained is filtered throughsilica (eluted with heptane) and then crystallized from an ethanol/ethermixture. After filtration, 2.9 g (69%) of an orange-coloured solid areobtained.

¹H NMR (CDCl₃): 1.21 (6H, s), 1.25 (6H, s), 1.65 (4H, s), 7.20 (1H Ar,d, J=8.25 Hz), 7.38 (1H Ar, dd, J=1.9 Hz, J=8.25 Hz), 7.51 (1H Ar, d,J=1.9 Hz).

(b) Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

Bromine (0.15 ml, 2.9 mmol) is added to a solution of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene diselenide (1.5 g,2.8 mmol) in THF (3 ml). The mixture is stirred at room temperature for2 h and the solvent is then removed. Copper iodide (2.15 g, 11.3 mmol),methyl 4-ethynylbenzoate (810 mg, 5 mmol) obtained according to Example1(b) and DMF (15 ml) are added. The reaction mixture is stirred at roomtemperature for 3 h and is then treated with ethyl ether and aqueousammonia solution. The organic phase is washed twice with water, driedover anhydrous magnesium sulphate and concentrated on a rotaryevaporator under vacuum at 40° C. The residue is recrystallized fromheptane and, after filtration, 1.8 g (75%) of a white powder areobtained. m.p.=90-1° C.

¹H NMR (CDCl₃): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 3.92 (3H, s),7.29 (1H Ar, d, J=8.3 Hz), 7.36 (1H Ar, dd, J=1.9 Hz, J=8.3 Hz), 7.48 to7.53 (3H Ar, m), 7.98 (2H Ar, d, J=8.5 Hz).

Example 54-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid

Lithium hydroxide (440 mg) is added to a solution of methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate(740 mg, 1.74 mmol), obtained in Example 4, in 15 ml of THF and 2 ml ofa water/methanol mixture (1/1). The reaction medium is refluxed for 8 h.It is then poured into an ethyl ether/water mixture, acidified to pH 1with concentrated hydrochloric acid solution and extracted with ethylether. After separation of the phases by settling, the organic phase iswashed twice with water, dried over anhydrous magnesium sulphate andconcentrated on a rotary evaporator under vacuum at 40° C. The residueis recrystallized from heptane. After filtration, 615 mg (86%) of awhite powder are obtained. m.p.=182° C.

¹H NMR (CDCl₃): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 7.29 (1H Ar,d, J=8.3 Hz), 7.36 (1H Ar, dd, J=1.9 Hz, J=8.3 Hz), 7.52 to 7.55 (3H Ar,m), 8.07 (2H Ar, d, J=8.5 Hz).

Example 6 Methyl2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate(a) Methyl 4-trimethylsilanylethynyl-2-hydroxybenzoate

In a manner similar to that of Example 1(a), starting with 4.00 g (14.4mmol) of methyl 4-iodo-2-hydroxybenzoate, 3.07 g (86%) of the expectedcompound are obtained in the form of an orange-coloured oil.

¹H NMR (CDCl₃): 0.06 (s, 9H), 3.75 (s, 3H), 6.76 (dd, 1H, J=8.2/1.5 Hz),6.87 (d, 1H, J=1.4 Hz), 7.56 (d, 1H, J=8.2 Hz), 10.53 (s, 1H).

(b) Methyl 4-ethynyl-2-hydroxybenzoate

3.07 g (12.4 mmol) of methyl4-trimethylsilanyl-ethynyl-2-hydroxybenzoate are mixed, in a 500 mlthree-necked flask, with 50 ml of THF, and 13.7 ml of atetrabutylammonium fluoride solution (1 M/THF) are added dropwise. Thereaction medium is stirred for 1 h at room temperature and is thenpoured into water and extracted with ethyl ether. After separation ofthe phases by settling, the organic phase is dried over magnesiumsulphate and concentrated. 2.48 g (100%) of a beige-coloured powder areobtained. m.p.=62° C.

¹H NMR (CDCl₃): 3.21 (s, 1H), 3.96 (s, 3H), 6.98 (dd, 1H, J=8.2/1.5 Hz),7.10 (d, 1H, J=1.3 Hz), 7.78 (d, 1H, J=8.2 Hz), 10.76 (s, 1H).

(c) Methyl2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

In a manner similar to that of Example 4(b), after reaction of 1.5 g(2.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenediselenide, in 2 ml of THF, with bromine (0.15 ml, 2.9 mmol), copperiodide (2.15 g; 11.3 mmol) and methyl 4-ethynyl-2-hydroxybenzoate (890mg; 5 mmol) in 10 ml of DMF are added. After purification on a column ofsilica (dichloromethane 10/heptane 90), 2.15 g (97%) of the expectedester derivative are obtained in the form of a yellow solid. m.p.=70° C.

1H NMR (CDCl₃): 1.28(d,12H); 1.69(s,4H); 3.95(s,3H); 6.94(dd,1H);7.04(d,1H); 7.26 to 7.37(m,2H); 7.51(d,1H); 7.77(d,1H); 10.77(s,1H).

¹³C NMR (CDCl₃): 31.8; 4*CH3/34.2; Cq/34.6; Cq/34.9; 2*CH2/52.4;CH3/75.1; Cq/101.6; Cq/111.9; Cq/119.7; CH/121.9; CH/124.5; Cq/127.0;CH/127.8; CH/128.1; CH/129.9; CH/130.4; Cq/144.7; C/146.7; Cq/161.2;Cq/170.1; Cq.

Example 72-Hydroxy-4-(5,5,8,8-tetramethyl)-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid

A solution of2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate(1.2 g; 2.72 mmol) obtained in Example 6(c) and sodium hydroxide (1.5 g;37.5 mmol) in 20 ml of THF is refluxed for 24 h. The reaction medium isthen poured into an ethyl acetate/water mixture, acidified to pH 1 withconcentrated hydrochloric acid solution and extracted once with ethylacetate. After separation of the phases by settling, the organic phaseis washed twice with water, dried over magnesium sulphate andconcentrated on a rotary evaporator under vacuum at 40° C. 1 g (86%) ofa yellow solid is obtained. m.p.=170° C.

¹H NMR (DMSO): 1.28(m,12H); 1.68(s,4H); 6.95(d,1H); 7.03(s,1H); 7.25 to7.37(m,2H); 7.51(s,1H); 7.83(d,1H).

¹³C NMR (DMSO): 31.8; 4*CH3/34.2; Cq/34.6; Cq/34.9; 2*CH2/76.0;Cq/101.5; Cq/119.7; CH/122.1; CH/124.4; Cq/127.1; Cq/127.9; CH/128.2;CH/130.9; CH/131.4; Cq/144.7; Cq/146.7; Cq/161.6; Cq/174.2; Cq.

Example 86-(4-Methoxymethoxyphenylethynylselanyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene(a) 1-Iodo-4-methoxymethoxybenzene

5 g (22.7 mmol) of 4-iodophenol are added to a suspension of 75% sodiumhydride (872 mg; 27.25 mmol) in 20 ml of dimethylformamide. The mixtureis stirred for 30 minutes at room temperature and 2.59 ml (34.1 mmol) ofmethoxymethyl chloride are then added. The solution is stirred for 2 hand the medium is then poured into an ethylacetate/water mixture. Afterseparation of the phases by settling, the organic phase is washed twicewith water, dried over magnesium sulphate and concentrated on a rotaryevaporator under vacuum at 40° C. 5.74 g (96%) of a colourless oil areobtained.

¹H NMR (CDCl₃): 3.45(s,3H); 5.13(s,2H); 6.80(d, 2H); 7.55(d,2H)

¹³C NMR (CDCl₃) 56.0; CH3/84.3; Cq/94.3; CH2/118.4; 2*CH/138.2;2*CH/157.0; Cq

(b) 1-Trimethylsilylethynyl-4-methoxymethoxybenzene

5.74 g (21.7 mmol) of 1-iodo-4-methoxymethoxybenzene, 100 ml oftriethylamine and a mixture of 1.53 g (2.18 mmol) ofdichloro-bis(triphenylphosphine)palladium and 831 mg (4.37 mmol) ofcopper iodide are introduced into a three-necked flask. 6.14 ml (43.5mmol) of trimethylsilylacetylene are then added and the medium isstirred for 48 h at room temperature. It is then poured into awater/ethyl acetate mixture. The organic phase is washed twice withwater and, after separation of the phases by settling, it is washed withmagnesium sulphate and concentrated.

(c) 1-Ethynyl-4-methoxymethoxybenzene

In a manner similar to that of Example 1(b), by reaction of the productobtained according to Example 8(b) with 50 ml of methanol and withpotassium carbonate for 15 h at room temperature, and after purificationon a column of silica (dichloromethane 20/heptane 80), 840 mg (24%) ofthe expected product are obtained in the form of a yellow oil.

¹H NMR (CDCl₃)) 3.00(s,1H); 3.46(s,3H); 5.17(s,2H); 6.97(d, 2H);7.42(d,2H).

¹³C NMR (CDCl₃): 56.1; CH3/76.1; Cq/83.5; CH/94.2; CH2/115.4; Cq/116.1;CH/133.6; CH/157.6; Cq

(d)6-(4-Methoxymethoxyphenylethynylselanyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene

In a manner similar to that of Example 4(b), after reaction of 1.3 g(2.44 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenediselenide, in 2 ml of THF, with bromine (0.13 ml, 2.5 mmol), copperiodide (1.86 g; 9.8 mmol) and 1-ethynyl-4-methoxymethoxybenzene (713 mg;4.4 mmol) in 10 ml of DMF are added. After purification on a column ofsilica (dichloromethane 20/heptane 80), 1.7 g (90%) of the expectedderivative are obtained in the form of a yellow oil.

¹H NMR (CDCl₃): 1.27(m,12H); 1.67(s,4H); 3.47(s,3H); 5.18(s,2H);6.98(dd,2H); 7.01 to 7.51(m,5H).

¹³C NMR (CDCl₃): 31.8; 4*CH3/34.1; Cq/34.5; Cq 34.9; 2*CH2/56.1;CH3/68.3; Cq/77.5; Cq/102.0; Cq/116.1; 2*Ch/116.7; Cq/125.3; Cq/133.3;2*CH/144.2; Cq/146.5; Cq/157.4; Cq.

Example 96-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid (a) Ethyl 6-trimethylsilylethynyl-3-pyridinecarboxylate

In a manner similar to that of Example 1(a), starting with 4 g (14.4mmol) of methyl 6-iodo-3-pyridinecarboxylate, 3.29 g (92%) of theexpected compound are obtained in the form of a beige-coloured powder.m.p.=55° C.

¹H NMR (CDCl₃) δ0.10 (s, 9H), 1.22 (t, 2H, J=7.1 Hz), 4.23 (q, 3H, J=7.1Hz), 7.33 (d, 1H, J=8.2 Hz), 8.06 (dd, 1H, J=8.1/2.1 Hz), 8.97 (d, 1H,J=2.1 Hz).

(b) Ethyl 6-ethynylnicotinate

In a manner similar to that of Example 6(b), starting with 3.29 g (13.3mmol) of ethyl 6-trimethylsilylethynylnicotinate, 1.00 g (43%) of theexpected compound is obtained in the form of beige-coloured flakes.m.p.=35° C.

¹H NMR (CDCl₃) δ1.42 (t, 3H, J=7.1 Hz), 3.33 (s, 1H), 4.42 (q, 2H, J=7.2Hz), 7.56 (d, 1H, J=8.1 Hz), 8.28 (dd, 1H, J=8.1/2.1 Hz), 9.18 (d, 1H,J=2.0 Hz)

(c) Ethyl6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate

In a manner similar to that of Example 4(b), after reaction of 1.84 g(3.4 mmol) of 5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthalenediselenide, in 2 ml of THF, with bromine (0.18 ml, 3.49 mmol), copperiodide (2.64 g; 13.9 mmol) and ethyl 6-ethynylnicotinate (1 g; 5.7 mmol)in 10 ml of DMF are added. 1.95 g (78%) of the expected derivative areobtained in the form of a brown oil.

¹H NMR (CDCl₃): 1.28 to 1.30(m,12H); 1.40(t,3H); 1.69(s,4H); 4.41(q,2H);7.12 to 7.59(m,4H); 8.24(dd,1H); 9.16(d,1H).

(d)6-(5,5,8,8-Tetramethy-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid

In a manner similar to that of Example 7, by reaction of 600 mg (1.36mmol) of ethyl6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinatein 30 ml of THF and 1 g of sodium hydroxide, and after trituration fromheptane, 200 mg (36%) of the expected compound are obtained in the formof a yellow solid. m.p.=128° C.

1H NMR (CDCl₃): 1.27 to 1.30(m,12H); 1.68(s,4H); 7.26 to 7.52(m,5H);8.32(d,1H); 9.26(s,1H)

¹³C NMR (CDCl₃): 31.8; 4*CH3/34.2; Cq/34.6; Cq/34.8; CH2/34.9; CH2/78.6;Cq/101.4; Cq/123.6; Cq/123.8; Cq/125.8; CH/127.8; CH/128.4; CH/128.5;137.9; CH/145.1; Cq/146.8; Cq/147.0; Cq/151.5; CH/169.0; Cq.

Example 10N-(4-hydroxyphenyl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzamide

A solution of 250 mg (0.63 mmol) of4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid obtained in Example 5, 169 mg (1.25 mmol) of1-hydroxybenzotriazole, 240 mg (1.25 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 82 mg (0.75mmol) of 4-aminophenol in 20 ml of THF is stirred at room temperaturefor 15 h. Water and ethyl acetate are then added. After stirring andseparation of the phases by settling, the aqueous phase is extractedwith ethyl acetate. The organic phases are then combined and washed withwater, dried over magnesium sulphate and concentrated on a rotaryevaporator under vacuum at 40° C. The product is purified on a column ofsilica (ethyl acetate 20/heptane 80). 200 mg (65%) of a white solid areobtained. m.p.=202° C.

1H NMR (DMSO): 1.23 (s, 6H); 1.25 (s, 6H); 1.64 (s, 4H); 6.72 to 6.76(d, 2H); 7.39 (c, 1H); 7.51 to 7.55 (d, 2H); 7.59 to 7.61 (d, 2H); 7.64to 7.67 (d, 2H); 7.95 to 7.98 (d, 2H); 9.28 (s, 1H); 10.10 (s, 1H).

Example 11 Methyl5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate(a) Methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate

In a manner similar to that of Example 1(a) starting with 7 g (26.6mmol) of methyl 5-iodo-2-pyridinecarboxylate, 4.25 g (68%) of theexpected compound are obtained in the form of an orange-coloured powder.m.p.=45° C.

¹H NMR (CDCl₃) δ0.28 (s, 9H), 4.01 (s, 3H), 7.87 (dd, 1H, J=8.1/2.0 Hz),8.08 (d, 1H, J=8.1 Hz), 8.77 (d, 1H, J=1.3 Hz).

(b) Methyl 5-ethynyl-2-pyridinecarboxylate

In a manner similar to that of Example 6(b), starting with 2.25 g (9.6mmol) of methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate, 380 mg(24%) of the expected compound are obtained in the form of a yellowpowder. m.p.=40-5° C.

1H NMR (CDCl₃) δ3.40 (s, 1H), 4.02 (s, 3H), 7.93 (dd, 1H, J=8.1/2.0 Hz),8.12 (d, 1H, J=8.1 Hz), 8.83 (d, 1H, J=1.9 Hz).

(c) Methyl5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate

In a manner similar to that of Example 4(b), after reaction of 918 mg(1.73 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene-2-diselenide in 2 mlof THF, with bromine (0.092 ml, 1.78 mmol), copper iodide (1.62 g; 8.5mmol) and methyl 5-ethynyl-2-pyridinecarboxylate (500 mg; 3.1 mmol) in10 ml of DMF are added. After trituration from heptane, 420 mg (32%) ofthe expected derivative are obtained in the form of a yellow solid.m.p.=75° C.

¹H NMR (CDCl₃): 1.28 to 1.29(d,12H); 1.69(s,4H); 4.02(s,3H); 7.27 to7.37(m,2H); 7.54(d,1H); 7.84(dd,1H); 8.11(d,₁H); 8.77(s,1H).

¹³C NMR (CDCl₃): 31.7; 4*CH3/34.2; Cq/34.6; Cq/34.8; 2*CH2/53.0;CH3/79.2; Cq/98.3; Cq/123.9; 2*Cq/124.5; CH/127.4; CH/128.2; CH/128.3;CH/138.7; CH/145.1; CH/145.8; Cq/146.9; Cq/151.6; CH/165.2; Cq.

Example 122-(4-Chlorophenylselanylethynyl)-5,5,8,8,tetramethyl-5,6,7,8-tetrahydronaphthalene

In a manner similar to that of Example 4(b), after reaction of 2 g (5.25mmol) of bis(4-chlorophenyl) diselenide in 5 ml of THF with bromine(0.266 ml, 5.15 mmol), copper iodide (4.11 g: 21.6 mmol) and6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (2.18 g; 10mmol) (described in patent application EP 0,661,258 A1) in 20 ml of DMFare added, and after purification on a column of silica (heptane), 1.85g (45%) of the expected derivative are obtained in the form of acolourless oil.

¹H NMR (CDCl₃): 1.28(s,12H); 1.68(s,4H); 7.26 to 7.30(m,4H); 7.46 to7.52(m,3H).

Example 13 Methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate(a) 5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene diselenide

In a manner similar to that of Example 4(a), by reaction of 4.4 g (15.8mmol) of 2-bromo-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene)with 22 ml of tert-butyllithium and selenium (1.33 g, 16.8 mmol) in 100ml of THF, 3.26 g (74%) of the expected selenated derivative areobtained in the form of a yellow solid. (m.p.=126° C.).

¹H NMR (CDCl₃): 1.14(6H, s), 1.23 (6H, s), 1.61 (4H, s), 2.35 (3H, s),7.05 (1H Ar, s), 7.55 (1H Ar, s).

(b) Methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

In a manner similar to that of Example 4(b), after reaction of 1.5 g(2.75 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenediselenide in 5 ml of THF, with bromine (0.15 ml, 2.9 mmol), copperiodide (2.1 g; 11.05 mmol), and methyl 4-ethynylbenzoate (790 mg; 4.94mmol) in 20 ml of DMF are added, and after trituration from heptane,1.57 g (70%) of the expected derivative are obtained in the form of awhite solid. m.p.=104° C.

¹H NMR (CDCl₃): 1.27 to 1.29(m,12H); 1.68(s,4H); 2.36(s,3H); 3.91(s,3H);7.12(s,1H); 7.50(d,2H); 7.73(s,1H); 8.00(d,2H).

¹³C NMR (CDCl₃): 21.4; CH3/32.3; 2*CH3/32.4; 2*CH3/34.5; Cq/34.8;Cq/35.5; 2*CH2/52.7; CH3/75.0; Cq/102.2; Cq/125.9; Cq/128.5; Cq/129.1;2*CH/129.8; Cq/130.1; 2*CH/131.5; 2*CH/134.9; Cq/144.7; Cq/145.3;Cq/167.0; Cq.

Example 144-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoicacid

In a manner similar to that of Example 7, by reaction of 1.35 g (3.07mmol) of methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoatein 20 ml of THF and 3 g of sodium hydroxide, and after trituration fromheptane, 1.05 g (80%) of the expected compound are obtained in the formof a white solid. m.p.=240° C.

¹H NMR (CDCl₃): 1.27 to 1.30(m,12H); 1.68(s,4H); 2.35(s,3H); 7.13(s,1H);7.50(d,2H); 7.71(s,1H); 8.00(d,2H).

¹³C NMR (CDCl₃): 20.5; CH3/31.5; 4*CH3/33.6; Cq/33.9; Cq/34.6;2*CH2/73.6; Cq/101.6; Cq/125.0; Cq/127.1; Cq/127.9; CH/128.3; CH/129.4;2*CH/130.5; 2*CH/133.8; Cq/143.9; 2*Cq/144.5; Cq/167.5; Cq.

Example 15Methyl-2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoate

In a manner similar to that of Example 4(b), after reaction of 1 g (1.78mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenediselenide in 5 ml of THF with bromine (0.092 ml, 1.78 mmol), copperiodide (1.36 g; 7.15 mmol) and methyl 4-ethynyl-2-hydroxybenzoate (566mg; 3.2 mmol) obtained according to Example 6(b) in 10 ml of DMF areadded, and after trituration from heptane, 715 mg (49%) of the expectedderivative are obtained in the form of a brown solid. m.p.=102° C.

¹H NMR (CDCl₃): 1.20(s,6H); 1.23(s,6H); 1.60(s,4H); 2.28(s,3H);3.87(s,3H); 6.87(dd,1H); 6.97(d,1H); 7.04(s,1H); 7.64(s,1H); 7.71(d,1H);10.70(s,1H).

¹³C NMR (CDCl₃): 20.7; CH3/31.7; 4*CH3/33.8; Cq/34.1; Cq/34.8;2*CH2/74.9; Cq/101.4; Cq/111.7; Cq/119.4; Cq/121.6; CH/125.1; Cq/128.4;2*CH/129.7; CH/130.3; Cq/134.2; Cq/144.1; Cq/144.7; Cq/161.1; Cq/169.9;Cq.

Example 162-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid

In a manner similar to that of Example 7, by reaction of 500 mg (1.1mmol) of methyl2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,in 20 ml of THF, with 500 mg of sodium hydroxide, 464 mg (99%) of theexpected compound are obtained in the form of a brown solid. m.p.=248°C.

¹H NMR (CDCl₃+DMSO): 0.89(s,6H); 0.92(s,6H); 1.30(s,4H); 1.96(s,3H);6.55(dd,1H); 6.60(s,1H); 7.31(s,1H); 7.43(d,1H); 10.96(sb,1H).

¹³C NMR (CDCl₃+DMSO): 20.6; CH3/31.6; 4*CH3/34.0; Cq/34.6; Cq/34.7;2*CH2/74.1; Cq/101.6; Cq/112.5; Cq/118.9; CH/121.3; CH/125.0; Cq/128.0;CH/128.3; CH/129.6; Cq/130.4; CH/133.9; Cq/144.0; Cq/144.0; Cq/144.5;Cq/161.4; Cq/171.9; Cq.

Example 17 Ethyl6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate

In a manner similar to that of Example 4(b), after reaction of 1 g (1.78mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenediselenide, in 5 ml of THF, with bromine (0.092 ml, 1.78 mmol), copperiodide (1.36 g; 7.15 mmol) and ethyl 6-ethynylnicotinate (463 mg; 2.64mmol) in 10 ml of DMF are added, and 1.06 g (88%) of the expectedderivative are obtained in the form of a brown solid. m.p.=95° C.

¹H NMR (CDCl₃): 1.20(s,6H); 1.24(s,6H); 1.34(t,3H); 1.61(s,3H);4.33(q,2H); 7.07(s,1H); 7.38(d,1H); 7.67(s,1H); 8.17(dd,1H); 9.08(d,1H).

¹³C NMR (CDCl₃): 13.9; CH3/20.9; CH3/31.5; 4*CH3/33.7; Cq/34.0; Cq/34.6;2*CH2/61.2; CH2/77.2; Cq/101.2; Cq/124.2; Cq/124.3; Cq/125.2; Cq/128.4;CH/129.4; CH/134.8; Cq/136.8; Cq/144.0; Cq/145.1; Cq/146.3; Cq/150.8;Cq/164.5; Cq.

Example 186-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid

In a manner similar to that of Example 7, by reaction of 800 mg (1.73mmol) of ethyl6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,in 20 ml of THF, with 800 mg of sodium hydroxide, and after purificationon a column of silica (ethyl acetate), 135 mg (19%) of the expectedcompound are obtained in the form of a yellow solid. m.p.=185° C.

¹H NMR (CDCl₃): 1.27(s,6H); 1.31(s,6H); 1.68(s,4H); 2.40(s,3H);7.15(s,1H); 7.26(s,1H); 7.49(d,1H); 7.74(s,1H); 8.32(d,1H); 9.25(s,1H).

¹³C NMR (CDCl₃): 21.7; CH3/32.2; 4*CH3/34.5; Cq/34.7; Cq/35.3;2*CH2/78.9; Cq/101.7; Cq/124.0; Cq/124.9; Cq/126.1; CH/129.1; CH/130.2;CH/135.6; Cq/1382; CH/144.8; Cq/145.9; Cq/147.6; Cq/152.0; CH/169.5; Cq.

Example 19N-(4-Hydroxyphenyl)-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)nicotinamide

In a manner similar to that of Example 10, by reaction of 300 mg (0.72mmol) of the6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)nicotinicacid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45mmol) of 1,3-dicyclohexylcarbodiimide and 95 mg (0.87 mmol) of4-aminophenol in 20 ml of THF, and after purification on a column ofsilica (ethyl acetate 20/heptane 80), 20 mg (6%) of a yellow solid areobtained. m.p.=172° C.

¹H NMR (DMSO): 1.17 to 1.19(m,12H); 1.56(s,4H); 2.27(s,3H); 6.68(d,2H);7.21(s,1H); 7.46(d,2H); 7.58(d,1H); 7.64(s,1H); 8.22(dd,1H);8.99(s,1H)9.30(s, 1H); 10.2(s, 1H).

¹³C NMR (DMSO): 31.6; 4*CH3/33.5; CH2/33.8; CH2/34.0; Cq/34.5,Cq/47.6;CH3/74.9; Cq/102.0; Cq/115.2; 2*CH/122.3; 2*CH/124.4; Cq/125.9;CH/128.7; CH/128.9; CH/130.4; Cq/134.8; Cq/136.1; CH/144.0; Cq/144.1;Cq/145.1; Cq/149.3; Cq/154.1; Cq/156.8; Cq.

Example 20N-Butyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide

In a manner similar to that of Example 10, 300 mg (0.72 mmol) of6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 63.5 mg (0.87 mmol)of butylamine in 20 ml of THF. After purification on a column of silica(ethyl acetate 20/heptane 80), 60 mg (17%) of a yellow solid areobtained. m.p.=172° C.

¹H NMR (CDCl₃): 0.97(t,3H); 1.27 to 1.37(m,12H); 1.37 to 1.46(m,4H);1.68(s,4H); 2.39(s,3H); 3.47(q,2H); 6.13(m,1H); 7.14(s,1H); 7.46(d,1H);7.74(s,1H); 8.07(dd,1H); 8.87(s, 1H).

¹³C NMR (CDCl₃): 31.8; CH3/20.2; CH2/21.2; CH3/31.7; 4*CH3/34.0;Cq/34.3; Cq/35.0; 2*CH2/40.0; CH2/76.2; Cq/101.2; Cq/124.7; Cq/126.0;CH/128.7; CH/129.7; CH/; CH/35.1; Cq/135.3; CH/144.3; Cq/145.4;Cq/145.5; Cq/; Cq.

Example 21Morpholin-4-yl-[6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-3-pyridyl]methanone

In a manner similar to that of Example 10, 300 mg (0.72 mmol) of6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinicacid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 75.7 mg (0.87 mmol)of morpholine in 20 ml of THF. After purification on a column of silica(ethyl acetate 20/heptane 80), 60 mg (17%) of a colourless oil areobtained.

¹H NMR (CDCl₃): 1.27 to 1.32(m,12H); 1.68(s,4H); 2.39(s,3H);3.81(sbr,8H); 7.13(s,1H); 7.45(d,1H); 7.71 to 7.75(m,2H); 8.61(d,1H).

¹³C NMR (CDCl₃): 21.2; CH3/31.8; 4*CH3/34.1; Cq/34.3; Cq/35.0;2*CH2/66.8; 4*CH2/75.5; Cq/101.1; Cq/124.7; Cq/126.0; CH/128.7;CH/129.4; Cq/129.7; CH/135.1; Cq/135.5; CH/144.3; Cq/144.5; Cq/145.4;Cq/148.3; CH/167.4; Cq.

Example 22 Methyl5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate

In a manner similar to that of Example 4(b), after reaction of 945 mg(1.68 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenediselenide, in 5 ml of THF, with bromine (0.092 ml, 1.78 mmol), copperiodide (1.32 g; 6.95 mmol) and methyl 5-ethynyl-2-pyridinecarboxylate(500 mg; 3.1 mmol) in 10 ml of DMF are added, and after trituration fromheptane, 1 g (73%) of the expected derivative is obtained in the form ofa yellow solid. m.p.=52° C.

¹H NMR (CDCl₃): 1.27 to 1.29(m,12H); 1.68(s,4H); 2.37(s,3H); 4.02(s,3H);7.14(s,1H); 7.71(s,1H); 7.85(dd,1H); 8.02(s,1H); 8.11(d,1H).

¹³C NMR (CDCl₃): 20.7; CH3/31.5; 2*CH3/31.6; 2*CH3/33.7; Cq/34.0;Cq/34.6; 2*CH2/52.7; CH3/78.9; Cq/98.1; Cq/123.7; Cq/124.2; CH/124.5;Cq/128.4; CH/128.5; CH/134.3; Cq/138.3; CH/144.0; Cq/144.9; Cq/145.5;Cq/151.2; CH/162.2; Cq.

Example 235-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylicacid

In a manner similar to that of Example 7, by reaction of 800 mg (1.73mmol) of methyl5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate,in 20 ml of THF, with 2 g of sodium hydroxide, and after triturationfrom heptane, 580 mg (65%) of the expected compound are obtained in theform of a white solid. m.p.=164° C.

¹H NMR (CDCl₃): 1.28(s,6H); 1.30(s,6H); 1.69(s,4H); 2.39(s,3H);7.16(s,1H); 7.69(s,1H); 7.93(d,1H); 8.17(dbr,1H); 8.66(sbr,1H).

¹³C NMR (CDCl₃): 21.2; CH3/31.8; 2*CH3/3.9; 2*CH3/34.1; Cq/34.3;Cq/34.9; 2*CH2/124.6; Cq/128.8; CH/129.3; CH/134.9; Cq/139.8; CH/144.4;2*Cq/145.5; 2*Cq.

Example 24[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]methanol

A 1M solution of diisobutylaluminium hydride in toluene (4 ml, 4 mmol)is added dropwise, at 0° C., to a solution of methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoateobtained according to Example 4 (750 mg, 1.8 mmol), in toluene (20 ml).The solution is stirred for 4 h at 0° C. and is then treated with adouble potassium sodium tartrate solution, filtered and taken up in amixture of ethyl ether and water. The organic phase is washed withwater, dried over magnesium sulphate and concentrated on a rotaryevaporator under vacuum at 40° C. 418 mg (60%) of a colourless oil areobtained.

¹H NMR (CDCl₃): 1.26(s, 6H), 1.28(s, 6H), 1.76(s, 4H), 4.67(s, 2H), 7.24to 7.37(m, 4H), 7.46(d, 2H, J=8.2 Hz), 7.52(d, 1H, J=1.9 Hz).

Example 25 Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate

In a manner similar to that of Example 1(c), by reaction of 234 mg (1.1mmol) of 6-ethynyl-1,1,4,4,-tetramethyl-1,2,3,4-tetrahydronaphthalene,in 5 ml of THF, with 2.5 M butyllithium (0.4 ml, 1 mmol) and2,2′-dithiobis(methyl benzoate) (267 mg; 0.8 mmol), and afterpurification on a column of silica (dichloromethane 30/heptane 70), theexpected derivative is obtained in the form of a white solid.

¹H NMR (CDCl₃): 1.28(6H, s), 1.29(6H, s), 1.69(4H, s), 3.91(3H, s),7.30(2H Ar, s), 7.49 to 7.54(3H Ar, m), 8.0(2H Ar, d, J=6.9 Hz).

Example 264-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol(a) 4-Trimethylsilylethynylphenyl acetate

In a manner similar to that of Example 1(a), starting with 4.63 g (17.7mmol) of 4-iodophenyl acetate, 3.72 g (90%) of the expected compound areobtained in the form of a yellow powder. m.p.=45° C.

¹H NMR/CDCl₃: 0.05(s; 9H); 2.10(s,3H); 6.84(dt,2H); 7.28(dt,2H).

¹³C NMR/CDCl₃: 0.00; 2*CH3/21.2; CH3/94.4; Cq/104.3; Cq/120.9; Cq/121.2;2*CH/133.2; 2*CH/150.7; Cq/169.1; Cq.

(b)4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenylacetate

In a manner similar to that of Example 4(b), after reaction of 1.39 g(2.4 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenediselenide, in THF, with bromine (0.22 ml, 4.3 mmol), copper iodide(1.82 g, 9.6 mmol) and 4-trimethylsilylethynylphenyl acetate ester (1 g;4.3 mmol) in DMF are added at 80° C. for 15 h, and after purification ona column of silica (dichloromethane 20/heptane 80), 220 mg (16%) of theexpected derivative are obtained in the form of a yellow oil.

¹H NMR/CDCl₃: 1.19(d,12H); 1.59(s,4H); 2.22(s,3H); 2.26(s,3H); 6.97 to7.02(m,3H); 7.39 to 7.42(dd,2H); 7.65(s,1H).

¹³C NMR/CDCl₃: 19.2; CH3/19.5; CH3/30.3; 4*CH3/32.4; Cq/32.7; Cq/33.4;CH2/33.5; CH2/68.7; Cq/99.9; Cq/119.5; Cq/120.1; 2*CH/124.2; Cq/126.7;CH/126.9; CH/131.0; 2*CH/133.0; Cq/142.5; Cq/143.5; Cq/138.0; Cq/167.5;Cq.

(c)4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol

A mixture of4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)phenylacetate (500 mg, 1.1 mmol) and potassium carbonate (160 mg, 1.1 mmol) inmethanol (20 ml) is stirred for 24 h at room temperature and is thentreated with ethyl ether and water. The organic phase is washed twicewith water, dried over anhydrous magnesium sulphate and concentrated ona rotary evaporator under vacuum at 40° C. The product is purified on acolumn of silica (ethyl acetate 20/heptane 80). 300 mg (66%) of a clearoil are obtained.

¹H NMR/CDCl₃: 1.25 to 11.27(m,12H); 1.66(s,4H); 2.35(s,3H); 6.77(d,2H);7.09(s,1H); 7.38(dd,2H); 7.73(s,1H).

¹³C NMR/CDCl₃: 20.3; CH3/31.4; 4*CH3/33.6; 2*Cq/34.6; 2*CH2/67.2;Cq/103.7; Cq/115.3; Cq/115.6; 2*CH/127.7; Cq/128.5; 2*CH/133.0;2*CH/133.6; Cq/143.6; Cq/143.9; Cq/156.0; Cq.

Example 27 Ethyl4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

In a manner similar to that of Example 4(b), after reaction of 1 g (1.5mmol) of4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenediselenide, in THF, with bromine (0.092 ml, 1.78 mmol), copper iodideand ethyl 4-trimethylsilylethynylbenzoate (644 mg; 2.8 mmol) in DMF areadded at 80° C. for 15 h. After purification on a column of silica(dichloromethane 20/heptane 80), 220 mg (16%) of the expected derivativeare obtained in the form of a yellow oil.

¹H NMR/CDCl₃: 1.29(s,6H); 1.37 to 1.43(m,9H); 1.65(q,4H); 4.39(q,2H);5.72(s,1H); 7.26(s,1H); 7.43(s,1H); 7.55(d,2H); 8.03(d,2H).

Example 28 Ethyl4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate

In a manner similar to that of Example 4(b), after reaction of 1 g (1.5mmol) of4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenediselenide, in THF, with bromine (0.092 ml, 1.78 mmol), copper iodideand ethyl 4-trimethylsilylethynylbenzoate (644 mg; 2.8 mmol) in DMF areadded at 80° C. for 15 h. After purification on a column of silica(dichloromethane 20/heptane 80), 420 mg (31%) of the expected derivativeare obtained in the form of a yellow oil.

¹H NMR/CDCl₃: 1.17(q,6H); 1.31(m,9H); 1.49 to 1.57(m,4H); 3.38(s,3H);4.25(q,2H); 5.10(s,2H); 7.08(d,1H); 7.14(d,1H); 7.41(d,2H); 7.88(d,2H).

Example 294-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoicacid

In a manner similar to that of Example 7, by reaction of 300 mg of ethyl4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoateester in 30 ml of THF with 500 mg of sodium hydroxide, and aftertrituration from heptane, the expected compound is obtained in the formof a white solid.

¹H NMR/CDCl₃: 1.28 (s, 6H); 1.39 (s, 6H); 1.66 (m, 2H); 3.51 (s, 3H);5.23 (s, 2H); 7.19 (d, 1H, J=1.8 Hz); 7.25 (d, 1H, J=1.8 Hz); 7.56(d,2H, J=8.5 Hz); 8.06 (d,2H, J=8.5 Hz).

Example 30[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]carbaldehyde

A mixture of[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]methanolobtained in Example 24 (280 mg, 0.7 mmol) and pyridinium dichromate (526mg, 1.4 mmol) in dichloromethane (10 ml) is stirred at room temperaturefor 4 h. After filtration through silica and concentration on a rotaryevaporator under vacuum at 40° C., 173 mg (63%) of the expected productare obtained in the form of a yellow oil.

¹H NMR/CDCl₃: 1.28 (s, 6H), 1.30 (s, 6H), 1.70 (s, 4H), 4.67 (s, 2H),7.23 (1H Ar, d, J=8.3 Hz), 7.29 (1H Ar, dd, J=1.9 Hz, J=8.3 Hz), 7.52 to7.59 (3H Ar, m), 7.84 (1H Ar, d, J=6.7 Hz); 9.99 (.H, s).

Example 31 Methyl 4-(4,4-dimethylthiochroman-8-ylselanylethynylbenzoate(a) 2-Bromo-1-(3-methylbut-2-enylthio)benzene

19.30 g (102.0 mmol) of 2-bromothiophenol, 160 ml of DMF and 15.50 g(112.0 mmol) of potassium carbonate are introduced into a three-neckedflask. 13 ml (112.0 mmol) of 1-bromo-3-methyl-2-butene are addeddropwise and the mixture is stirred at room temperature for two hours.The reaction medium is poured into water and extracted with ethylacetate, and the organic phase is separated out after settling has takenplace, washed with water, dried over magnesium sulphate and evaporated.26.00 g (99%) of the expected compound are collected in the form of anorange-coloured oil.

¹H NMR/CDCl₃ d 1.65 (s, 3H), 1.73 (s, 3H), 3.56 (d, 2H, J=7.7 Hz), 5.32(td, 1H, J=7.7/1.4 Hz), 6.96 to 7.06 (m, 1H), 7.22 to 7.26 (m, 2H), 7.52(d, 1H, J=7.7 Hz).

(b) 4,4-Dimethyl-8-bromothiochroman

26.00 g (102.0 mmol) of 2-bromo-1-(3-methylbut-2-enylthio)benzene, 180ml of toluene and 23.20 g (122.0 mmol) of para-toluenesulphonic acid areintroduced into a three-necked flask. The reaction medium is refluxedfor four hours and evaporated to dryness. The residue is taken up inaqueous sodium hydrogen carbonate solution and extracted with ethylacetate, and the organic phase is separated out after settling has takenplace, dried over magnesium sulphate and evaporated. The residueobtained is purified by chromatography on a column of silica eluted withheptane. 20.00 g (76%) of the expected compound are collected in theform of an orange-coloured oil.

¹H NMR (CDCl₃) d 1.33 (s, 6H), 1.94 (t, 2H, J=6.0 Hz), 3.04 (t, 2H,J=6.1 Hz), 6.89 (t, 1H, J=7.9 Hz), 7.34 (d, 2H, J=7.9 Hz).

(c) 4,4-Dimethyl-8-thiochroman diselenide

One crystal of iodine, magnesium (208 mg, 8.56 mmol) and a few drops ofa solution of 4,4-dimethyl-8-bromothiochroman (2 g, 7.78 mmol) in ethylether (15 ml) are heated until the organomagnesium reagent has beeninitiated. The rest of the solution is then added dropwise. The reactionmedium is heated for 2 h and selenium (615 mg, 7.78 mmol) is then addedat room temperature. The stirring is continued for 30 min and 1N HClsolution is then added. The reaction mixture is treated with ethylether. The organic phase is washed twice with water, dried overanhydrous magnesium sulphate and concentrated on a rotary evaporatorunder vacuum at 40° C. Ethanol and sodium hydroxide are added to the oilobtained. The mixture is stirred vigorously for a few minutes and isthen concentrated on a rotary evaporator under vacuum at 40° C. Theproduct is purified on a column of silica (dichloromethane 20/heptane80). 300 mg (15%) of a white solid are obtained.

¹H NMR (CDCl₃): 1.33 (6H, s), 1.96 (2H, m), 3.09 (2H, m), 6.93 (1H Ar,t, J=7.8 Hz), 7.26 (1H Ar, dd, J=7.8 Hz, J=1.3 Hz), 7.47 (1H Ar, dd,J=7.8 Hz, J=1.3 Hz).

(c) Methyl 4-(4,4-dimethylthiochroman-8-ylselanyl-ethynyl)benzoate

In a manner similar to that of Example 4(b), after reaction of 300 mg(1.9 mmol) of 4,4-dimethyl-8-thiochroman diselenide, in 2 ml of THF,with bromine (0.117 ml, 2.2 mmol), copper iodide (780 mg) and methyl4-ethynylbenzoate (562 mg; 3.5 mmol) in 20 ml of DMF are added, andafter purification on a column of silica (dichloromethane 20/heptane80), the expected derivative is obtained in the form of a yellow solid.

¹H NMR (CDCl₃): 1.35 (6H, s), 1.97 (2H, m), 3.10 (2H, m), 3.93 (3H, s),7.07 (1H Ar, t, J=7.8 Hz), 7.31 (1H Ar, dd, J=7.8 Hz, J=1.3 Hz), 7.55(2H Ar, d, J=8.5 Hz) 7.59 (1H Ar, dd, J=7.8 Hz, J=1.3 Hz), 8.00 (2H Ar,d, J=8.5 Hz).

Example 324-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoicacid

In a manner similar to that of Example 2, by reaction of methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoatein THF, and after crystallization from heptane, the expected derivativeis obtained in the form of a white solid.

¹H NMR (CDCl₃): 1.28 (6H, s), 1.29 (6H, s), 1.70 (4H, s), 7.30 (2H Ar,s), 7.43 to 7.50 (3H Ar, t), 7.99 (2H Ar, d, J=7.5 Hz).

Formulation Examples EXAMPLE 1

Various pharmaceutical and cosmetic formulations based on the compoundsaccording to the invention are described below.

A - ORAL ROUTE (a) 0.2 g tablet Compound of Example 1 10.001 g  Starch0.114 g Dicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc0.010 g Magnesium stearate 0.005 g

In this example, the compound of Example 1 can be replaced with the sameamount of one of the compounds of Examples 4, 6, 11, 13 or 15.

(b) Drinkable suspension in 5 ml vials Compound of Example 3 20.001 gGlycerol 0.500 g 70% sorbitol 0.500 g Sodium saccharinate 0.010 g Methylp-hydroxybenzoate 0.040 g Flavouring, qs Purified water qs 5 ml (c) 0.8g tablet Compound of Example 2 0.500 g Pregelatinized starch 0.100 gMicrocrystalline cellulose 0.115 g Lactose 0.075 g Magnesium stearate0.010 g

In this example, the compound according to Example 2 can be replacedwith the same amount of one of the compounds of Examples 6, 11, 14 or28.

(d) Drinkable suspension in 10 ml vials Compound of Example 3 0.200 gGlycerol 1.000 g 70% sorbitol 1.000 g Sodium saccharinate 0.010 g Methylp-hydroxybenzoate 0.080 g Flavouring, qs Purified water qs 10 ml B -TOPICAL ROUTE (a) Ointment Compound of Example 2 20.020 g Isopropylmyristate 81.700 g Fluid liquid petroleum jelly 9.100 g Silica (“Aerosil200” sold by Degussa) 9.180 g (b) Ointment Compound of Example 1 0.300 gWhite petroleum jelly codex 100 g (c) Nonionic water-in-oil creamCompound of Example 1 0.100 g Mixture of emulsifying lanolin alcohols,waxes and oils (“anhydrous eucerin” sold by BDF) 39.900 g Methylp-hydroxybenzoate 0.075 g Propyl p-hydroxybenzoate 0.075 g Steriledemineralized water qs 100 g

In this example, the compound according to Example 1 can be replacedwith the same amount of one of the compounds of Examples 4, 16, 22, 27or 32.

(d) Lotion Compound of Example 3 0.100 g Polyethylene glycol (PEG-400)69.900 g 95% ethanol 30.000 g (e) Hydrophobic ointment Compound ofExample 1 0.300 g Isopropyl myristate 36.400 g Silicone oil (“Rhodorsil47V300” 36.400 g sold by Rhône-Poulenc) Beeswax 13.600 g Silicone oil(“Abil 300.000 cst” 100 g sold by Goldschmidt) (f) Nonionic oil-in-watercream Compound of Example 2 1.000 g Cetyl alcohol 4.000 g Glycerylmonostearate 2.500 g PEG stearate 502.500 g Karite butter 9.200 gPropylene glycol 12.000 g Methyl p-hydroxybenzoate 0.075 g Propylp-hydroxybenzoate 0.075 g Sterile demineralized water 100 g

In this example, the compound according to Example 2 can be replacedwith the same amount of one of the compounds of Examples 5, 9, 12, 19and 32.

Test of Activity

Results of differentiation tests on mouse embryonic teratocarcinomacells (F9) to identify the RAR-agonist molecules as described in SkinPharmacol. 3, pp. 256-267, 1990.

After treatment with the compounds of the examples cited in thefollowing table, the mouse embryonic teratocarcinoma F9 cellsdifferentiate into endodermal cells. This differentiation ischaracterized by the secretion of the plasminogen activator into theculture medium.

The activity of the product is expressed by the AC₅₀ value representingthe concentration of the test product which produces half of the maximumamount of plasminogen activator secreted.

Examples F9 AC₅₀ (nM) Compound 1 20 Compound 2 1 Compound 4 4 Compound 521 Compound 16  33 Compound 18  34

These results indicate that the compounds of Examples 1, 2, 4, 5, 16 and18 are RAR-agonist compounds.

TABLE A

n = 0 if Y is oxygen

TABLE B

n = 0 if Y is oxygen

What is claimed is:
 1. Bi-aromatic compounds linked via aheteroethynylene bond, corresponding to the general formula (I) below:

in which: Ar represents a radical

R₁ represents a halogen atom, —CH₃, —CH₂—OR₇, —OR₇, —COR₈ or a polyetherradical, R₂ and R₃, taken together, form a 5- or 6-membered ring,optionally substituted with at least one methyl, R₄ and R₅ represent H,a halogen atom, linear or branched C₁-C₂₀ alkyl, —OR₇ or a polyetherradical, R₇ represents H, linear or branched C₁-C₁₀ alkyl or —COR₉, R₈represents H, linear or branched C₁-C₁₀, alkyl, —OR₁₀ or

R₉ represents linear or branched C₁-C₁₀ alkyl, R₁₀ represents H, linearor branched C₁-C₂₀ alkyl, mono- or polyhydroxyalkyl, allyl, optionallysubstituted aryl or aralkyl, or a sugar residue, r′ and r″, which may beidentical or different, represent H, C₁-C₁₀ alkyl, mono- orpolyhydroxyalkyl, optionally substituted aryl, an amino acid or peptideresidue or, taken together with the nitrogen atom, form a heterocycle, Xrepresents a divalent radical which, from right to left or vice-versahas the formula:

in which: Y represents O, S(O)_(n) or Se(O)_(n′), n and n′ being 0, 1,or 2, and the salts of the compounds of formula (I) when R₁ represents acarboxylic acid function, as well as the optical isomers of the saidcompounds of formula (I).
 2. Compounds according to claim 1, in the formof a salt of an alkali metal or alkaline-earth metal, or alternativelyof zinc or of an organic amine.
 3. Compounds according to claims 1,wherein the C₁-C₁₀ alkyl radical is selected from the group consistingof the methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, 2-ethylhexyland octyl radicals.
 4. Compounds according to claim 1, wherein thelinear or branched C₁-C₂₀ alkyl radical is selected from the groupconsisting of the methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl,hexadecyl and octadecyl radicals.
 5. Compounds according to claim 1,wherein the C₃-C₁₂ cycloalkyl radical is selected from the groupconsisting of the cyclopropyl, cyclopentyl, cyclohexyl,1-methylcyclohexyl and 1-adamantyl radicals.
 6. Compounds according toclaim 1, wherein the polyether radical is selected from the groupconsisting of the methoxymethoxy, methoxyethoxy and methoxyethoxymethoxyradicals.
 7. Compounds according to claim 1, wherein themonohydroxyalkyl radical is selected from the group consisting of the2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl radicals. 8.Compounds according to claim 1, wherein the polyhydroxyalkyl radical isselected from the group consisting of the 2,3-dihydroxypropyl,2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl radicals and thepentaerythritol residue.
 9. Compounds according to claim 1, wherein thearyl radical is a phenyl radical optionally substituted with at leastone halogen atom, a hydroxyl or a nitro function.
 10. Compoundsaccording to claim 1, wherein the aralkyl radical is selected from thegroup consisting of the benzyl and phenethyl radicals optionallysubstituted with at least one halogen atom, a hydroxyl or a nitrofunction.
 11. Compounds according to claim 1, wherein the sugar residueis selected from the group consisting of the glucose, galactose, mannoseand glucuronic acid residues.
 12. Compounds according to claim 1,wherein the amino acid residue is selected from the group consisting ofthe residues derived from lysine, from glycine or from aspartic acid.13. Compounds according to claim 1, wherein the heterocyclic radical isselected from the group consisting of the piperidino, morpholino,pyrrolidino and piperazino radicals, optionally substituted in position4 with a C₁-C₆ alkyl or a mono- or polyhydroxyalkyl.
 14. Compoundsaccording to claim 1, wherein the halogen atom is selected from thegroup consisting of fluorine, chlorine and bromine.
 15. Compoundsaccording to claim 1, of the general formula:

in which: Ar′ represents a radical of formula:

R₁, R₄, R₅ and X being as defined in claim 1, R₁₁, R₁₂, R₁₃ and R₁₄,which may be identical or different, represent H or —CH₃, and n is 1 or2.
 16. Compounds according to claim 1, selected from the groupconsisting of: Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthlysulphanylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoic acid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphonylethynyl)benzoate, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthyloxyethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxyethynyl) benzoicacid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphanylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoic acid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphonylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoic acid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylsulphinylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphinylethynyl)benzoic acid, Methyl4-(5,5,8,8,-tetramethyl-5,6,7,8-tetra-hydro-2-naphthylselanylethynyl)benzoate,4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid, Methyl2-hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,2-Hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,6-(4-Methoxymethoxyphenylethynylselanyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene,N-(4-Hydroxyphenyl)-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzamide,2-(4-Chlorophenylselanylethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,Methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid, Methyl2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,2-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]methanol, Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate, Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoate, Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoate,4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoic acid,4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoic acid,4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoic acid,4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol, Ethyl4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,Ethyl4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl-ethynyl)benzoate,4-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,4-(4-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid, Ethyl4-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate, Ethyl4-(3-methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,4-(3-Methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,4-(3-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid, Ethyl4-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,4-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]carbaldehyde, Methyl4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoate, and4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoic acid.
 17. A method of making a medical product comprising mixinga compound according to claim 1, with a medicinal medium.
 18. A methodof treating at least one of dermatological complaints, dermatologicalcomplaints with an inflammatory and/or immunoallergic component of therheumatic or respiratory type, cardiovascular complaints andopthalmological disorders comprising administering an effective amountof a compound of claim 1 to an individual in need of said treatment. 19.Pharmaceutical composition comprising a pharmaceutically acceptablemedium and at least one compound according to claim
 1. 20. Compositionaccording to claim 19, wherein the concentration of said at least onecompound is between 0.001% and 5% by weight relative to the total weightof the composition.
 21. Cosmetic composition comprising a cosmeticallyacceptable medium and at least one compound according to claim
 1. 22.Composition according to claim 21, wherein the concentration of said atleast one compound is between 0.001 and 3% by weight relative to thetotal weight of that composition.
 23. A method of body or hair hygienetreatment comprising applying a cosmetic composition as definedaccording to claim 21 to said body or hair.